On September 25 and 26, 1997, the National Institute of Neurologic Disorders and Stroke (NINDS) and the National Institute
of Child Health and Human Development (NICHD) held an international workshop on the use of near infrared spectroscopy (NIRS)
for brain monitoring in infants and children. This technology utilizes light in the near infrared range to determine cerebral
oxygenation, blood flow, and metabolic status of the brain. The instrument consists of fiberoptic bundles or optodes placed
either on opposite sides of the head or close together at acute angles. Light enters the head through one optode and a fraction
of the photons are captured by a second optode and conveyed to a measuring device. Multiple light emitters and detectors can
also be placed in a headband to provide tomographic imaging of the brain.

The method is based on the fact that light in the near infrared range (700 to 1000 nm) can pass through skin, bone, and other
tissues relatively easily, especially in the neonatal head. It utilizes the characteristic absorption bands of oxygenated
and deoxygenated hemoglobin, and the mitochondrial enzyme cytochrome oxidase (or cytochrome aa3). Cytochrome oxidase is the
terminal member of the mitochondrial respiratory chain, and is necessary for conversion of ADP to ATP. It has a very high
affinity for oxygen in both neonate and adult, thus reduction of cytochrome oxidase occurs only after oxygen saturation falls
to very low levels and the majority of hemoglobin is deoxygenated.

Five years previously, the NINDS held a workshop on the same topic, bringing together experts in the technical development
of the instrumentation and clinicians who had some experience in using or potentially could use this new technology. At that
time, discussion focused primarily on technical issues, and several goals were established such as accurate determination
of path length and absolute quantification. In the last five years a great deal of progress has been made on many of those
technical issues. While some problems of quantitation still remain to be solved, the availability of a usable clinical instrument
is now a reality. Therefore, the purpose for the 1997 workshop was to examine the different types of NIRS instruments currently
available, to discuss the benefits and limitations of each one, to determine what improvements are still needed, and to suggest
what studies are needed to determine if the use of NIRS can improve clinical care, especially of the neonate.

The strengths and weaknesses of several different methods of using near infrared light to detect cerebral oxygenation, blood
flow, and energy status were presented. Because of scattering properties of almost all tissue types within the brain, any
measurement scheme has to take into account the effects of tissue scattering on the signal detected. For any NIRS method to
be useful, it must be highly accurate, be able to measure absorption at several different wavelengths which are clinically
relevant, and thereby to quantify blood oxygen saturation and blood concentration values to a high degree of accuracy.

The continuous wave (CW) method measures only the intensity of light, is very reliable, but currently allows only relative
or trend measurements due to the lack of information available about path length. To address this problem, in current CW instruments,
multiple separations of optodes placed around the head operating simultaneously are required. This allows for a path length
correction, but only for a homogeneous brain. The signal to noise ratio is reasonable with this technique. The depth of brain
tissue which can be measured from the surface is varied typically from 1-3 cm.

The time-resolved technique consists of emitting a very short laser pulse into an absorbing tissue and recording the temporal
response (time of flight) of the photons at some distance from the laser source. This method allows for separation of the
effects due to absorbance of light from the effects due to scattering of light, using a mathematical approximation that is
based on diffusion theory. The time of-flight method permits differentiation of one tissue from another. In addition, the
scattering component provides useful information. Functional imaging is an exciting application of the time-of-flight method,
because scattering changes which can be mapped optically, in addition to hemoglobin status, may illuminate the electrical
and vascular interaction which determines the functional status of the brain. One disadvantage of this technique which still
needs to be addressed is the large size, the relatively slow data collection (minutes) and analysis, so that information obtained
at bedside is not displayed instantaneously, but rather a few minutes later.

The frequency domain method is based on the modulation of a laser light at given frequencies. This method allows for correction
of the detected signal for the different scattering effects of the fluid and tissue components of the brain, using data processing
algorithms. Moreover, the phase and amplitude shifts can be used for good localization of the signal. The hemoglobin saturation
can be measured, to + 5 % in models and +. 10% in piglets since path length information is directly measured. Problems include
noise and leakage associated with the high frequency signal, but the devices are very compact and appropriate for bedside/isolette
use. This technology can be further refined to provide better accuracy, and to provide clinical utility.

There is a competition between the response of the device and the accuracy (e.g. quantitation and resolution) of the measurements.
The two extremes are the CW method which has a very fast response, but registers relative changes, and the time of flight
method which needs extensive data processing, but provides more accurate measurements because of its ability to better localize.
The frequency domain or phase modulation technology, although with less resolution than that of time of flight, potentially
provides adequate measurements of brain oxygenation in a clinically acceptable amount of time. Thus, the frequency domain
or phase modulation technology is potentially the best candidate for the ICU/NICU setting and for bedside usage, and will
result in brain oximeters of a similar precision, size and patient acceptability as finger pulse oximeter, but with brain
tissue oximeter capability. The time of flight method, which enables one to explore different information provided by the
measured signals, could also become a valuable tool in research and clinical environments.

The presenter for this topic reviewed animal studies which used NIRS to assess levels of hemoglobin oxygenation, cerebral
hemodynamics, and the status of cytochrome oxidase. Hemoglobin oxygenation and cytochrome aa3 oxygenation have been correlated
with changes in cerebral blood flow. The effects of physiologic changes such as hyperventilation, hypoxia, ischemia and cardiopulmonary
bypass have been evaluated, and the accuracy of the measurements have been tested. It was noted that animal studies showed
that decreases in hemoglobin oxygenation and increases in hemoglobin deoxygenation correlated well with various levels of
hypoxia, and with the degree of cytochrome aa3 oxidation when FIO2 levels were low (below 8%). Generally, the brain tissue
oxygen saturation values lay between those of arterial and venous (sagital sinus) blood; equivalent to approximately 2/3 venous
and 1/3 arterial.

The next speaker described NIRS evaluations of infants intrapartum by CW oximetry. A drop in fetal heart rate corresponded
with a fall in oxyhemoglobin and an increase in deoxyhemoglobin. Vasodilation in response to hypoxia resulted in increased
total hemoglobin in the brain. A good correlation between NIRS intrapartum data and scalp pH at birth has been shown. Because
continuous path length measurements have not yet been included in these studies, they have thus far been relative to a within-subject
baseline and have not allowed quantitative measurements. Thus phase modulation methods are desirable for intrapartum quantification
of hemoglobin saturation.

An important question to be addressed by intrapartum use of NIRS is whether changes in mean cerebral hemoglobin saturation,
hemodynamic responses to hypoxia, or cytochrome oxidase status are highly correlated with intrapartum brain injury. Equally
important is what the timing of these changes indicates about the timing of the insult and the possibility of a therapeutic
window between exposure to an insult and irreversible brain damage. The possibility of prepartum fetal studies was also presented
for discussion.

Examples of applications of NIRS to neonatal assessments were described, such as using NIRS to look at changes in cerebral
oxyhemoglobin during treatment for respiratory distress, and the effect of partial occlusion of the jugular veins on cerebral
circulation. One study was described in preterm infants randomized to either indomethacin or ibuprofen for treatment of a
patent ductus arteriosus. NIRS was used to measure blood flow, blood volume, and response to changes in arterial carbon dioxide
tension. Treatment with indomethacin, unlike ibuprofen, was associated with reduced cerebral blood flow and volume.

Hypoxic ischemic brain injury is a major problem for the approximately 15,000 infants annually undergoing cardiac surgery
for correction of congenital heart disease. NIRS has been effectively used for brain oxygenation monitoring during cardiac
surgery. A continuous wave technique was used, which does not measure scattering and is not quantitative. Data was collected
continuously intra-operatively. With cooling, there was a drop in cerebral oxygen consumption. At the onset of cardiopulmonary
bypass there was a drop in total hemoglobin, largely due to hemodilution. The decrease in oxyhemoglobin concentration at circulatory
arrest continued throughout the cooling period and remained relatively constant after the onset of low-flow bypass, followed
by hyperoxygenated reperfusion following the bypass and with rewarming. The decrease in cytochrome oxidase continued throughout
the cooling phase, dropped further during circulatory arrest, and was delayed in recovery despite a rapid intravascular oxygenation
recovery. Once there are more well defined clinical studies including follow up correlations, this technology could be applied
to identify the infant at risk for imminent brain injury during cardiac surgery.

In the post-operative period, infants are often paralyzed and heavily sedated and inaccessible for examination. Cardiac rhythm
disturbances and pulmonary complications may occur, and NIRS would allow monitoring of brain blood flow and oxygenation during
this period.

The next speaker described an important application of NIRS: imaging of brain activity, including sensorimotor responses which
would be particularly useful in neonates where unresponsiveness to functional activation might be diagnostic of a severe insult
or poor prognosis. The current resolution with available instruments is comparable to PET (and not as good as MRI), but should
improve with better instrumentation and better algorithms. Experiments showing a consistent increase in the oxidation of cytochrome
aa3 during non-imaging functional activation, indicate that regional imaging of the redox state of cytochrome oxidase might
indicate localized cerebral malfunction.

NIRS using phase modulation imaging may also be used to obtain measurements of light scattering of depolarizing neurons to
produce a functional image. The temporal resolution of this application is in milliseconds, much faster than for current NIR
signals. Questions to be addressed include whether spreading electrical depressions and peri-infarct stabilizations occur
in neonatal cerebral ischemia. Changes in light scattering seen by NIRS should correspond to changes in diffusion-weighted
MRI. Thus, NIRS functional imaging may be an early way to indicate cerebral edema or other cellular malfunctioning. For these
rapid changes, technical instrumentation must be refined to respond more rapidly before studies are done to ascertain its
clinical usefulness.

Another potential functional application of light scattering imaging NIRS is in detection of spontaneous fluctuations of background
depolarization signals, which may be related to functional connections between two regions. In infants, the fluctuations of
these signals in the resting state are not systematic, and probably depend on the sleep or wake state. The position of the
babies' heads may influence blood return. Factors such as these must be included in clinical research designs. Work on this
promising application of NIRS technology should be encouraged, and validation studies over extended intervals should be performed
as soon as technical development permits.

Insults such as hypoxia, ischemia, and probably infection as well, set up a cascade of events that includes rapid depolarization
of neurons which liberates glutamate presynaptically. There is an over-activation of multiple glutamate receptors post synaptically,
causing mobilization of intracellular calcium in neurons and other cells in the central nervous system. Free radical injury
is responsible for continuing the injury process, and nitric oxide synthase activity appears at this stage.

In the pre-term infant, the white matter is especially vulnerable after global hypoxic/ischemic events, which may result in
periventricular leukomalacia. In contrast, in the term infant, a similar insult tends to destroy the deep gray nuclei, the
basal ganglia and the thalamus. This changing regional vulnerability is very important. Inhibition of the mitochondrial respiratory
chain may lead to the escape of cytochrome oxidase from the mitochondria, which is believed to trigger a cascade in the cytoplasm
leading to programmed cell death or apoptosis. Early detection of these events may have implications for the timing of therapeutic
intervention. In both cases imaging of injured regions of the brain is possible using NIRS with further technical refinements
and subsequent clinical validation.

In the Neonatal ICU, current bedside measures include EEG, brain stem evoked responses, cranial ultrasounds, and hemodynamic
measurements using Doppler flow meters. NIRS oximetry and functional imaging could be used in various locations, such as the
delivery suite or the operating room. It is a portable bedside technology which could be coupled with other cerebral imaging
tools such as MRI and PET scans to provide useful information about the global as well as focal metabolic status of the brain.
NIRS can provide an early diagnosis, even within a few hours of life, of cerebral blood flow increases, energy metabolism
decreases, and brain functional activity. Diffusion-weighted MRI is another imaging tool which is useful to detect evolving
lesions in the brain, but cannot be used at the bedside or in a very fragile or unstable patient, as can NIRS.

NIRS can be applied not only after a defined insult is known to have occurred, but also in a baby who exhibits clinical signs
of encephalopathy, the cause of which is often unknown. NIRS imaging must be sensitive enough to image regional changes and
gray and white matter differences in the premature and full term infant. Neonatal management issues could be addressed using
bedside NIRS; for example, what is a critical level of hemoglobin deoxygenation for babies on cardiopulmonary bypass, do transfusions
optimize brain oxygenation in infants, or what is the best ventilatory therapy in the NICU to minimize brain damage? When
babies with respiratory disease drop their PO2 levels, but there is no change in cytochrome oxidase, is that prognostically
reassuring? Babies who are paralyzed or sedated also would be candidates for monitoring with NIRS, especially when treatments
need to be monitored for efficacy and toxicity to the brain.

The participants in the workshop agreed that as new therapies are becoming available with potential for neuroprotection, NIRS
could potentially discriminate between infants at high and low risk for poor outcome in the first few hours of life, and could
be used to monitor the safety and efficacy of treatment interventions. Validation studies now must be done to demonstrate
correlation of the results of NIRS monitoring with other imaging modalities which diagnose energy failure, and to establish
the predictive power for cognitive and sensori-motor outcomes. To accomplish this validation of NIRS, a population at risk
for poor neurologic outcome must be followed longitudinally and results compared with currently acceptable measures of brain
function.

Vascular and metabolic responses to stimulation now provide functional imaging. In addition, a goal of further development
of this technology is to provide functional neuroimaging using light scattering due to propagation of electrical impulses.
Failure of functional activation shown by NIRS imaging may provide an effective measure of imminent brain energy failure,
using a simple stimulus such as movement of a limb to observe regional functional activation. If some of the potentially reversible
early signals of mitochondrial energy failure which involve light scattering changes can be recognized, then it may be possible
to test intervention therapies.

There are still remaining areas of this technology which need refinement. Without instruments which provide path length measurement
or multiple wavelengths, quantitative measurement of tissue oxygenation and cytochrome aa3 cannot be reliably ascertained.
However, considerable progress has been made in quantitation. In 1992, NIRS was semi-quantitative. Now, the time of flight,
phase modulation and scanning continuous wave instruments are essentially quantitative for CBF and cerebral oxygen saturation.
For the accuracy of these techniques to improve, more sophisticated imaging algorithms must be developed to take into account
the heterogeneity of the skull and its contents and allow for separate imaging of white and gray matter.

A number of instruments for brain oximetry are currently undergoing animal and/or human subject studies. Many CW instruments
relying upon correction give only trend indication. At least two phase modulation systems for clinical use in infants are
currently available, and laboratory devices are also available. Time of flight instruments are also available for clinical
research and are being developed for imaging. Active commercial development of clinical oximeters and imagers can be expected
in two to three years.